Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma

Abstract

Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers.

Discovery and development of differentially methylated regions in human papillomavirus‐related oropharyngeal squamous cell carcinoma

“…NID2 is known as a component of the basement membrane that stabilizes the extracellular matrix (ECM) network. Expression of NID2 suppresses migration and inhibits metastasis by suppressing the EGFR/AKT and integrin/FAK/PLCγ pathways . HOXB4, as a hematopoietic transcription factor, downregulates the expression of Prdm16, which is a proto‐oncogene necessary for self‐renewal and maintenance of murine hematopoietic stem cells .…”

“…Expression of NID2 suppresses migration and inhibits metastasis by suppressing the EGFR/AKT and integrin/FAK/ PLCγ pathways. 32 HOXB4, as a hematopoietic transcription factor, downregulates the expression of Prdm16, which is a proto-oncogene necessary for self-renewal and maintenance of murine hematopoietic stem cells. 33 The other eight frequently methylated candidates (CCDC181, DPP4, BEND4, CTNND2, ELMO1, SFMBT2, C1QL3, MIR129-2) confirmed in our study have also shown hypermethylation in other malignancies (Table 1).…”

Functional characterization of a candidate tumor suppressor gene, Mirror Image Polydactyly 1, in nasopharyngeal carcinoma

“…The previously established wild‐type (WT) MIPOL1 stable‐expressing clones were used . The MIPOL1 WT and two truncation mutants, ΔN100 and ΔC200‐442, were established and subcloned to pLVX‐EF1α lentiviral expression vector (modified from pLVX‐CMV; Clontech) in HONE‐1 and NPC/HK1 as described …”

“…5 The MIPOL1 WT and two truncation mutants, ΔN100 and ΔC200-442, were established and subcloned to pLVX-EF1α lentiviral expression vector (modified from pLVX-CMV; Clontech) in HONE-1 and NPC/HK1 as described. 17 Two-dimensional and three-dimensional colony formation assay…”

“…The transwell migration and invasion assays were performed, as previously described. 17,19 In brief, 2 × 10 5 cells were seeded onto the migration and invasion chambers (BD Biosciences, San Jose, CA) with serum-free medium. The bottom of the chambers containing 10% serum-enriched medium served as a chemoattractant.…”